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Abstract
Objectives To investigate the effectiveness and safety of TCZ (tocilizumab) monotherapy for chronic periaortitis (CP) patients at acute active stage.
Methods Twelve patients with definite or possible diagnosis of CP were enrolled and received intravenous infusions of TCZ (8 mg/kg) every 4 weeks for at least 3 months. Clinical features, laboratory and imaging findings were recorded at baseline and during the follow-up. The primary endpoint was the rate of partial and complete remission after 3 months TCZ monotherapy and the secondary endpoint was the frequency of treatment related adverse events.
Results Three patients (27.3%) achieved partial remission and seven patients (63.6%) obtained complete remission after 3 months TCZ treatment. The total remission rate achieved 90.9%. All patients reported improvement in clinical symptoms. Inflammatory markers such as erythrocyte sedimentation rate and C reactive protein decreased to normal levels after TCZ treatment. Nine patients (81.8%) showed remarkable shrinkage of perivascular mass greater than or equal to 50% on CT.
Conclusion Our study showed that TCZ monotherapy contributed to remarkable clinical and laboratory improvement in CP patients and could be an alternative treatment option for CP.
- autoimmunity
- autoimmune diseases
- anti-inflammatory agents, non-steroidal
- inflammation
- low back pain
Data availability statement
All data relevant to the study are included in the article or uploaded as online supplemental information.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
The traditional treatment of chronic periaortitis (CP) is glucocorticoids or combined with conventional immunosuppressive agents. We conducted a prospective single-arm study to investigate the effectiveness and safety of tocilizumab (TCZ) monotherapy for CP patients.
WHAT THIS STUDY ADDS
Improvements of clinical symptoms, laboratory parameters and reduction of perivascular mass were observed in patients with CP after 3 months TCZ monotherapy.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
TCZ monotherapy could be an alternative treatment with remarkable effectiveness and safety for CP patients.
Introduction
Chronic periaortitis (CP) is characterised by the presence of soft tissue density mass that develops around the thoracic aorta, abdominal aorta or iliac arteries, with predominance in middle-aged or elderly males.1 The pathogenic mechanism of CP has not been fully elucidated so far. Chronic inflammatory infiltration in tissues promotes expansion and differentiation of fibrocytes, eventually leading to fibrosis.2 3 Currently, glucocorticoids are the first-line therapy, which could be combined with conventional immunosuppressive agents.4 It has been reported that interleukin-6 (IL-6) acts as an inflammatory mediator and a potential target of therapy for CP and other fibroinflammatory disorders.5–7 Tocilizumab (TCZ), a recombinant humanised monoclonal antibody against IL-6 receptor (IL-6R), could inhibit IL-6 mediated signal transduction by blocking the binding of IL-6 to soluble and membrane-bound IL-6R, thereby reducing pathological inflammatory responses. Nevertheless, the application of TCZ for CP treatment was rarely reported in sporadic cases.5 8 Therefore, we conducted this prospective single-arm study to investigate the effectiveness and safety of TCZ monotherapy for CP patients at acute active stage.
Methods
Patient enrollment and treatment
Twelve patients with a definite or possible diagnosis of CP were enrolled at Peking Union Medical College Hospital for this study which was registered on ClinicalTrials.gov (NCT05133895). All patients enrolled were newly diagnosed and naive to treatment with steroids or immunosuppressive drugs. Two patients (No.1 and No.3) had undergone surgical resection but still had remaining perivascular mass. The presence of hydroureter and hydronephrosis was observed in eight patients and D–J tube implantation was applied in four patients due to ureteral obstruction. The clinical diagnosis of CP was established based on the following diagnostic criteria: (1) imaging findings show soft tissue density mass surrounding the thoracic aorta, abdominal aorta or iliac arteries in the absence of aneurysmal dilation and (2) histopathological findings show fibrous tissue with chronic inflammatory infiltrate comprised of lymphocytes and plasma cells.9 Patients who fulfilled (1) but without histopathological examination were perceived as possible CP. Secondary forms of CP related to drugs, infections, malignancies, Erdheim-Chester disease, definite IgG4-related disease or other autoimmune diseases were excluded.
Patients received intravenous infusions of TCZ (8 mg/kg) at inclusion and then every 4 weeks for at least 3 months. Biological samples were obtained by venous blood collection and then examined in the clinical laboratory of Peking Union Medical College Hospital. Clinical features and laboratory findings were recorded at baseline and during the follow-up, as presented in online supplemental materials.
Supplemental material
Definition of endpoints
All the patients had a systematic imaging evaluation at both baseline and the third-month visit. Imaging results were evaluated independently by a rheumatologist and a radiologist and discordant readings of the imaging were resolved by consensus or through a third doctor. Imaging improvement was converted into the ratio of perivascular mass shrinkage by evaluating two dimensions of greatest change on CT before and after TCZ treatment. The primary endpoint was the rate of partial and complete remission after 3 month TCZ monotherapy. The secondary endpoint was the frequency of treatment related adverse events. Partial remission was defined as obtaining alleviation of symptoms and normalisation of inflammatory markers including erythrocyte sedimentation rate (ESR) and C reactive protein (CRP), with perivascular mass shrinkage on imaging greater than or equal to 30% but less than 70%. Further, complete remission was defined as achieving alleviation of symptoms and normalisation of inflammatory markers accompanied by mass shrinkage greater than or equal to 70%. Patients with mass shrinkage less than 30% were regarded as having no remission, regardless of alleviation of symptoms or normalisation of inflammatory markers.
Statistical analysis
Normally distributed data were presented as mean±SD and data of non-normal distribution were presented as median with the IQR. Paired t-test and Wilcoxon signed rank test were used for statistical analysis.
Results
Demographic and clinical characteristics of patients with CP at baseline
Ten male and two female CP patients were enrolled in our study whose demographic and clinical characteristics at baseline were presented in table 1. The median age was 52.5 (39–66) years old. Six patients had a definite diagnosis of CP and the other six patients had a possible diagnosis of CP. Among these 12 patients, the median duration was 3 months at baseline since the onset of clinical symptoms which mainly manifested as abdominal pain and low back pain. According to the involvement of artery, these patients could be classified into four types: abdominal aorta (2 cases, 16.7%), iliac artery (1 case, 8.3%), abdominal aorta and iliac artery (7 cases, 58.3%) and thoracic aorta (2 cases, 16.7%). Extravascular organ involvement included ureters involvement (7 cases, 58.3%) and mediastinum involvement (2 cases, 16.7%) (table 1).
Demographic and clinical characteristics of patients with chronic periaortitis at baseline
Treatment response after three-month TCZ monotherapy
Patient No.2 lost the third-month follow-up. Both of decreased inflammatory markers and alleviation of symptoms were observed but imaging examination was not performed during the first 2 months. At a subsequent hospital visit of the sixth month, we came to know he had stopped the fourth TCZ infusion due to quarantine by the epidemic, then had a recurrence of serum creatinine sharp elevation and received percutaneous nephrostomy. Thus, remaining 11 patients were enrolled for following analysis.
Three patients (27.3%) achieved partial remission and seven patients (63.6%) obtained complete remission after 3-month TCZ monotherapy treatment (table 2). The total remission rate achieved 90.9%. Both of two patients with only the thoracic aorta/artery involved achieved complete remission (100.0%). One patient with involvement of the abdominal aorta alone achieved complete remission (50.0%) and the other patient achieved partial remission (50.0%). Out of the six patients with involvement of the abdominal aorta and iliac artery, four patients achieved complete remission (66.7%) and two patients achieved partial remission (33.3%). Patient No.12 with only the iliac artery involvement failed to achieve remission according to our defined criteria while a mass shrinkage of 20% along with ESR and CRP normalisation was observed. These patients could also be divided into two groups by IL-6 levels at baseline. In the group with normal IL-6 levels at baseline, four patients achieved complete remission (80.0%) and one patient achieved partial remission (20.0%). In the group with elevated IL-6 levels at baseline, three patients achieved complete remission (50.0%), two patients achieved partial remission (33.3%) and one patient had no remission (16.7%) (table 2).
Treatment response of CP patients to 3-month TCZ monotherapy
All the patients reported relief of clinical symptoms after TCZ treatment (table 2). Patient No.7 reported relief of abdominal pain but still suffered from low back pain and haematuria. The symptoms of abdominal pain, low back pain and haematuria were once temporarily aggravated after first TCZ infusion in Patient No.10. Then he reported a remarkable relief of pain but still presented with haematuria. Both ESR and CRP decreased significantly after TCZ treatment, with ESR from 34 (27–79) mm/hour to 2 (1–4) mm/hour (p<0.01) and CRP from 12.73 (7.02–43.22) mg/L to 0.21 (0.11–1.61) mg/L (p<0.01) (table 2, figure 1A,B). The above-normal levels of ESR in nine patients at baseline returned to normal levels after TCZ treatment. Elevated CRP in eight patients at baseline subsided to a very low level after treatment. White cell count also lowered after TCZ treatment (6.85±1.72×109 /L vs 5.13±1.02×109 /L, p<0.05) (table 2, figure 1C). Besides, IgG level after TCZ treatment was lower compared with baseline (13.74±3.76 g/L vs 10.79±3.52 g/L, p<0.01), so was C3 (1.38±0.39 g/L vs 0.83±0.37 g/L, p<0.001) and C4 (0.34±0.07 g/L vs 0.12±0.09 g/L, p<0.001) (table 2, figure 1D–F). Five patients had normal IL-6 levels and the other 6 patients had elevated IL-6 levels at baseline. IL-6 was elevated from 7.20 (3.30–17.00) pg/mL at baseline to 20.00 (12.50–32.96) pg/mL after TCZ treatment (p<0.05) (table 2, figure 1G). A shrinkage of perivascular mass was observed in all the 11 patients after 3 months TCZ treatment. Nine patients (81.8%) showed a remarkable shrinkage of perivascular mass greater than or equal to 50% on CT (figure 1H–J). Patient No.7 and No.10 were qualified for removal of D–J drainage tube after overall assessment. Transient elevation of alanine aminotransferase and aspartate aminotransferase was observed in two patients (No.8 and No.10) after initial TCZ infusion, which resumed to the normal level after extra liver-protective treatment. No other treatment-related adverse events occurred during the follow-up.
Inflammatory markers and imaging at baseline and after 3-month TCZ treatment. (A) ESR at baseline: 34 (27–79) mm/hour vs after 3-month TCZ treatment: 2 (1–4) mm/h, p<0.01; (B) CRP at baseline: 12.73 (7.02–43.22) mg/L vs after 3-month TCZ treatment: 0.21 (0.11–1.61) mg/L, p<0.01; (C) WCC at baseline: (6.85±1.72)×109/L vs after 3-month TCZ treatment: (5.13±1.02)×109 /L, p<0.05; (D) IgG level at baseline:13.74±3.76 g/L vs after 3- month TCZ treatment: 10.79±3.52 g/L, p<0.01; (E) C3 at baseline: 1.38±0.39 g/L vs after 3-month TCZ treatment: 0.83±0.37 g/L, p<0.001; (F) C4 at baseline: 0.34±0.07 g/L vs after 3-month TCZ treatment: 0.12±0.09 g/L, p<0.001; (G) IL-6 at baseline: 7.20 (3.30–17.00) pg/mL vs after 3-month TCZ treatment: 20.00 (12.50–32.96) pg/mL, p<0.05; (H) The percentage of soft tissue density mass shrinkage for each patient after 3-month TCZ treatment; (I) Contrast-enhanced abdominal CT of patient No.11 at baseline and after 3-month TCZ treatment, (a) at the abdominal aorta level; (b) at the iliac artery level; (c) the ureter involvement. (J) Contrast enhanced abdominal CT of patient No.9 at baseline and after 3-month TCZ treatment, (a) at the bifurcation of iliac arteries level; (b) at the iliac artery level. *p<0.05, **p<0.01, ***p<0.001. CRP, C reactive protein; ESR, erythrocyte sedimentation rate; C3, complement 3; C4, complement 4; IL-6, interleukin-6; TCZ, tocilizumab; WCC, white cell count.
Clinical outcome and treatment strategy during the follow-up after three months
Regular follow-up of these patients is still ongoing. Detailed information of clinical outcome and treatment strategy during the follow-up was listed in online supplemental table 1). Seven patients have maintained complete remission, three patients have maintained partial remission, and one patient has achieved partial remission by the sixth-month visit. Four patients have not yet reached the 1 year follow-up timing. Since 3-month TCZ monotherapy induced remission in most patients, TCZ of lengthened infusion intervals combined with methotrexate was usually applied as the maintaining therapy after 3 months TCZ treatment. Some patients switched to steroids combined with traditional immunosuppressive agents during the follow-up. Hydronephrosis exacerbation was presented in patient No.7 after D–J drainage tube removal at the fourth month, then the therapy of TCZ combined with methotrexate was replaced by prednisolone combined with cyclophosphamide. Patient No.11 switched to the alternative therapy of prednisolone combined with cyclophosphamide after 3 months TCZ monotherapy for economic reasons. Although inflammatory markers decreased significantly in patient No.12 after 3 months TCZ monotherapy, he failed to achieve remission because of limited radiological improvement. Therefore, alternative therapy of prednisolone combined with mycophenolate mofetil was applied and he achieved partial remission with the mass shrinkage of approximately 50% at the sixth-month visit. As mentioned above, patient No.2 lost follow-up from third to fifth months. At the sixth-month visit, TCZ combined with prednisolone and methotrexate was applied due to the presence of elevated inflammatory markers and hydronephrosis. Symptom alleviation and normalisation of inflammatory markers were observed but hydronephrosis still remained at the 1-year follow-up visit.
Supplemental material
Discussion
Current medical treatment for CP was mainly steroids or combined with various immunosuppressants. In fact, some patients may have contraindications for steroids such as severe psychosis and diabetes, or have fear appeals for steroids side effects, in which case steroids are not applicable, thus demanding new therapeutic alternatives with comparable efficacy and safety.
A study by Vaglio et al demonstrated the elevated serum IL-6 level and marked IL-6 expression by T cells, B cells, histiocytes as well as fibroblasts in tissues of CP patients, suggesting IL-6 as an important inflammatory mediator in CP pathogenesis and potential target of therapy. Besides, TCZ proves to be effective in treating large vessel vasculitides, which share the characteristics of large artery involvement and pronounced adventitial inflammation with CP.10–12 However, there is little literature on the application of TCZ for CP management. It has been reported that TCZ monotherapy induced sustained clinical and laboratory remission in a patient unable to tolerate glucocorticoids and in another case of retroperitoneal fibrosis, without occurrence of infections or other side effects.5 8 In our study, 90.9% of CP patients treated with TCZ monotherapy achieved remission, among which 63.6% of patients achieved complete remission. Inflammatory markers such as ESR and CRP decreased significantly after 3 months TCZ monotherapy. A total of 100.0% of patients and 83.3% of patients achieved remission in the group with normal IL-6 levels and elevated IL-6 levels at baseline, respectively. TCZ monotherapy had considerable effectiveness for CP patients, whether the IL-6 levels were normal or elevated at baseline. Besides, the type of artery involvement may affect the response to TCZ monotherapy since differential response rates among groups divided by artery involvement were observed in our study, although larger cohorts are required to validate this point. The increase of IL-6 after TCZ treatment probably attributes to inhibited IL-6R-mediated elimination other than enhanced synthesis, which coincides with the normalisation of inflammatory markers via the inhibition of IL-6 signalling through IL-6R.13
Although we focused on the effectiveness of short-term TCZ monotherapy for CP, we continue to follow-up our patients after 3 months. According to the follow-up data we have collected up to now, seven patients maintain complete remission and four patients maintain partial remission (online supplemental table 1). After 3 months TCZ treatment, methotrexate was usually added to the therapy in order to assist the gradually lengthened intervals of TCZ infusion or even withdrawal of TCZ in cases of sustainable remission. Steroids combined with traditional immunosuppressive drugs could be considered as the alternative therapeutic regimen in cases where the treatment of TCZ failed to attain good effect.
To our knowledge, this is the first prospective single-arm study to investigate the effectiveness of TCZ monotherapy for CP with advantages of evaluating remission from both laboratory and radiological aspects, thus providing evidence for clinical decision-making. One limitation of our study is lack of using (18)F-fluorodeoxyglucose-positron emission tomography (FDG-PET) to evaluate the metabolic activity of perivascular tissue. Previous studies revealed that FDG-PET was complementary to single CT assessment for better delineation of perivascular inflammation and better evaluation of disease activity.14–16 In our study, FDG-PET was performed in four patients at baseline to assist the establishment of clinical diagnosis. Given the higher cost of FDG-PET, those patients took CT examination instead of FDG-PET at the third-month visit for image-based disease activity monitoring. Another limitation is the limited sample size since larger sample size could make the results of comparison between specified groups more convincing. Besides, due to the limited duration of follow-up, the questions of whether achieved clinical and laboratory remission by TCZ monotherapy could be sustained and the frequency of relapse still await future studies to clarify.
Our study showed that TCZ monotherapy could be an effective alternative treatment for CP. Researches based on larger sample size and longer follow-up are warranted to further confirm the effectiveness of TCZ for CP management.
Data availability statement
All data relevant to the study are included in the article or uploaded as online supplemental information.
Ethics statements
Patient consent for publication
Ethics approval
This study was approved by the ethics board of Peking Union Medical College Hospital (ZS-2747). Participants gave informed consent to participate in the study before taking part.
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Contributors AW is the first author of this paper. YF and WZ are corresponding authors of this papaer. YF and WZ designed and supervised this study. YF, WZ, LP and JZ enrolled patients. AW, ZL, HL, YP and JL helped collect data. AW performed statistical analysis and wrote this manuscript. YF is responsible for the overall content as guarantor.
Funding This work was supported by National High Level Hospital Clinical Research Funding [2022-PUMCH-A-005, B-013, C-006], CAMS Innovation Fund for Medical Sciences (CIFMS) (2021-1-I2M-003,2022-I2M-C&T-B-005), Dongcheng District Outstanding Talent Nurturing Program (2022-dchrcpyzz-67) and National Key Research and Development Programme of China (2022YFC2703104).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.